Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma
Thale Kristin Olsen, … , David B. Sykes, Ninib Baryawno
Thale Kristin Olsen, … , David B. Sykes, Ninib Baryawno
Published August 9, 2022
Citation Information: JCI Insight. 2022;7(17):e153836. https://doi.org/10.1172/jci.insight.153836.
View: Text | PDF
Research Article Oncology Therapeutics

DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma

  • Text
  • PDF
Abstract

Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multiomic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening, and transcriptomic data across more than 700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of less than 10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in 3 neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma, and we propose this combination for clinical testing.

Authors

Thale Kristin Olsen, Cecilia Dyberg, Bethel Tesfai Embaie, Adele Alchahin, Jelena Milosevic, Jane Ding, Jörg Otte, Conny Tümmler, Ida Hed Myrberg, Ellen M. Westerhout, Jan Koster, Rogier Versteeg, Han-Fei Ding, Per Kogner, John Inge Johnsen, David B. Sykes, Ninib Baryawno

×

Figure 1

DHODH is highly expressed in neuroblastoma, and expression correlates with disease stage, prognosis, and survival.

Options: View larger image (or click on image) Download as PowerPoint

DHODH is highly expressed in neuroblastoma, and expression correlates w...
(A) Top 15 accumulated metabolites in neuroblastoma cell lines compared with other solid tumor cell lines of the Cancer Cell Line Encyclopedia (CCLE) metabolomics data set. Metabolite enrichment in neuroblastoma is quantified as variable importance in projection scores generated through partial least-squares discriminant analysis. (B) DHODH expression in solid tumor cell lines of the CCLE data set, grouped by primary disease. Black lines represent median values. (C) DHODH expression in primary pediatric tumor samples of the TARGET data set. Black lines represent median values. ****: P < 0.0001 (as evaluated by 1-way ANOVA with multiple comparisons). ALL, acute lymphatic leukemia; AML, acute myeloid leukemia. (D) Overall survival in 498 patients with neuroblastoma (SEQC-498 data set), separated by median DHODH expression. Red, DHODH above median (high); black, DHODH below median (low). Groups are compared using log-rank test. (E) DHODH expression in 498 neuroblastoma samples (SEQC-498 data set). DHODH expression is significantly higher in the MYCN-amplified tumors as evaluated by 1-way ANOVA with multiple comparisons. TPM, transcripts per million; RPKM, reads per kilobase million; RPM; reads per million; HR, high-risk; MNA, MYCN-amplified; NHR, non–high-risk; NMNA, non–MYCN-amplified. (F) DHODH expression levels in high-risk, non–MYCN-amplified tumors. High/low groups are identified using the KaplanScan feature of the R2 database (http://r2.amc.nl). Groups were compared using Student’s 2-tailed t test. (G) Kaplan-Meier curve showing the survival of the groups in F. Note that the “highest DHODH group” (n = 9) is associated with a particularly poor overall survival. Bonferroni method is used to correct for multiple testing.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts